Sodium valproate ameliorates diabetes-induced fibrosis and renal damage by the inhibition of histone deacetylases in diabetic rat

Recent reports emphasize the contribution of histone deacetylases (HDACs) in the pathogenesis of diabetic renal injury and fibrosis. Valproic acid (VPA) is a first-line drug used for the treatment of epilepsy and migraine as well as established as a HDAC inhibitor. The present study was aimed to evaluate the anti-fibrotic and renoprotective effects of VPA in diabetic nephropathy (DN). Diabetes was induced by single injection of STZ (50 mg/kg), whereas VPA at the doses of 150 and 300 mg/kg/day was administered for 8 consecutive weeks by oral route in Sprague Dawley rats. The renal injuries and fibrosis were assessed by histology, fibrosis specific staining and fibroblast activation by a transmission electron microscope, while expression of proteins of interest was evaluated by western blotting and immunohistochemistry. VPA treatment ameliorated the histological alterations as well as fibrosis, and decreased the expression of TGF-beta 1, CTGF, alpha-SMA, fibronectin, collagen I, COX-2, ICAM-1 and HDAC4/5/7. Further, VPA treatment significantly increased histone H3 acetylation and MMP-2 expression. The present study clearly established that VPA treatment ameliorates the renal injury and fibrosis in diabetic kidney by preventing the myofibroblast activation and fibrogenesis by HDAC inhibition and associated mechanisms, thereby improving the profibrotic and anti-fibrotic protein balance. (C) 2015 Elsevier Inc. All rights reserved.